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United States Patent |
5,565,614
|
Klauke
,   et al.
|
October 15, 1996
|
2,4,5-trihalogeno-and 2,3,4,5-tetrahalogenobenzene derivatives
Abstract
2,4,5-Trihalogenobenzene derivatives of the formula
##STR1##
is which R is --COOH, --COCl, --COF, --CN, --CONH.sub.2, --CH.sub.2 OH,
--CH.sub.2 Cl, --CHCl.sub.2, --CCl.sub.3 or --CHO,
R.sup.1 is H, Cl or F, and
R.sup.2 is Cl or F,
it only being possible for R.sup.1 or R.sup.2 to be F, and processes for
their preparation starting from benzonitriles reacted with potassium
fluoride. The novel compounds are intermediates for antibacterials such as
quinolone carboxylic acids.
Inventors:
|
Klauke; Erich (Odenthal, DE);
Petersen; Uwe (Leverkusen, DE);
Grohe; Klaus (Odenthal, DE)
|
Assignee:
|
Bayer Aktiengesellschaft (Leverkusen, DE)
|
Appl. No.:
|
419969 |
Filed:
|
April 7, 1995 |
Foreign Application Priority Data
| Jun 04, 1984[DE] | 34 20 796.1 |
Current U.S. Class: |
562/849 |
Intern'l Class: |
C07C 051/58 |
Field of Search: |
562/849
|
References Cited
U.S. Patent Documents
3230268 | Jan., 1966 | Kobayashi et al.
| |
3485865 | Dec., 1969 | Richter et al.
| |
4439620 | Mar., 1984 | Klauke et al.
| |
4549994 | Oct., 1985 | Hagemann et al.
| |
4556658 | Dec., 1985 | Grohe et al.
| |
4582948 | Apr., 1986 | Tank et al.
| |
4791225 | Dec., 1988 | Irikura et al.
| |
4792618 | Dec., 1988 | Bieron et al.
| |
Foreign Patent Documents |
0057844 | Aug., 1982 | EP.
| |
2503269 | Aug., 1979 | DE.
| |
0028493 | Nov., 1969 | JP.
| |
8035161 | Mar., 1983 | JP.
| |
9184149 | Oct., 1984 | JP.
| |
0023358 | Feb., 1985 | JP.
| |
0036453 | Feb., 1985 | JP.
| |
0977963 | Dec., 1964 | GB.
| |
2142018 | Jan., 1985 | GB.
| |
0007267 | Dec., 1987 | WO.
| |
Other References
Birchall, J. Metal, J. Chem. Soc. (C) (7) 1341-2, 1971.
Organicum, 3 Aufl. (1964), p. 438.
J. I. DeGraw et al., J. Cehm. Eng., vol. 13, 587-8 (1968).
J. Med. Chem 26, 1116-1122 (1983).
Japanese Laid Open (Kokai) Patent Publication No. 150543 (1983) Abstract.
Japanese Laid Open (Kokai) Patent Publication No. 233089 (1985) (Abstract).
Japanese Laid Open (Kokai) Patent Publication No. 72885 (1985) (Abstract).
Yokobson et al, Chemical Abstracts, vol. 64, Colms. 14124-5 (1966).
Chisso, Chemical Abstracts, vol. 100, #51279p (1984).
|
Primary Examiner: Killos; Paul J.
Attorney, Agent or Firm: Sprung Horn Kramer & Woods
Parent Case Text
This application is a continuation of application Ser. No. 08/284,331,
filed Aug. 2, 1994, now allowed, which is a division of Ser. No.
07/968,603 filed Oct. 29, 1992 now U.S. Pat. No. 5,362,909; which is a
division of Ser. No. 07/763,027 filed Sep. 20, 1991 now U.S. Pat. No.
5,200,548; which is a division of Ser. No. 07/459,876 filed Jan. 2, 1990
now U.S. Pat. No. 5,072,038; which is a continuation of Ser. No.
06/735,502 filed May 17, 1985, now abandoned.
Claims
We claim:
1. A process for the preparation of 2,4,5-trifluorobenzoyl fluoride,
comprising reacting 2,4-dichloro-5-fluorobenzoyl chloride with potassium
fluoride or with hydrofluoric acid prior to the reaction with potassium
fluoride in a solvent at elevated temperature.
2. A process for the preparation of 2,3,4,5-tetrahalogenobenzene derivative
of the formula
##STR51##
in which R is --COCl or --COF,
R.sup.1 is Cl or F, and
R.sup.2 is Cl or F
comprising reacting 2,3,4,5-tetrachlorobenzoyl chloride or
2,3,4,5-tetrachlorobenzoyl fluoride with potassium fluoride in a solvent
at elevated temperature to yield a compound of said formula wherein R is
--COF and thereafter optionally reacting said compound wherein R is --COF
with SiCl.sub.4 to yield a compound of said formula wherein R is --COCl.
3. The process according to claim 2, wherein the reaction with SiCl.sub.4
is carried out in the presence of AlCl.sub.3.
Description
The present invention relates to 2,4,5-trihalogeno- and
2,3,4,5-tetrahalogenobenzene derivatives and process for their
preparation. The compounds according to the invention are valuable
intermediates for the synthesis of highly active antibacterial
medicaments.
2,4,5-Trihalogeno- and 2,3,4,5-tetrahalogenobenzene derivatives of the
formula (I)
##STR2##
in which R represents --COOH, --COCl, --COF, --CN, --CONH.sub.2,
--CH.sub.2 OH, --CH.sub.2 Cl, --CHCl.sub.2, --CCl.sub.3 or --CHO,
R.sup.1 represents H, Cl or F and
R.sup.2 represents Cl or F,
it only being possible for R.sup.1 or R.sup.2 to be F, have been found.
The following may be particularly mentioned:
2,4,5-trifluorobenzoyl fluoride;
2,3,4-trifluoro-5-chlorobenzoyl fluoride;
2,4,5-trifluoro-3-chlorobenzoyl chloride;
2,4-difluoro-3,5-dichlorobenzoyl fluoride.
It has also been found that the 2,4,5-trihalogeno- and
2,3,4,5-tetrahalogenobenzene derivatives of the formula (I)
##STR3##
in which R represents --COOH, --COCl, --COF, --CN, --CONH.sub.2,
--CH.sub.2 OH, --CH.sub.2 Cl, --CHCl.sub.2, --CCl.sub.3 or --CHO,
R.sup.1 represents H, Cl or F and
R.sup.2 represents Cl or F,
it only being possible for R.sup.1 or R.sup.2 to be F, are obtained by
reacting 2,3,4,5-tetrachlorobenzonitrile with potassium fluoride in a
solvent at elevated temperature, and converting the resulting nitriles
into the compounds of the formula (I) in a manner known per se.
It has also been found that 2,3,4,5-tetrahalogenobenzene derivatives of the
formula (II)
##STR4##
in which R' represents --COCl or --COF, and
R.sup.1 represents Cl or F,
can be obtained by reacting 2,3,4,5-tetrachlorobenzoyl chloride or
2,3,4,5-tetrachlorobenzoyl fluoride (see European Patent No. 57,844),
where appropriate after fluorination with hydrofluoric acid, with
potassium fluoride in a solvent at elevated temperature.
The quantity of potassium fluoride to be used depends on the number of
chlorine atoms which are to be exchanged. At least one mole of KF is used,
but in general 1.1-1.5 mole, for 1 chlorine atom. A maximum of 2 moles of
KF is used for 1 chlorine; beyond this, the quantity of KF has virtually
no effect on the degree of fluorination, and the process becomes
uneconomic. However, it is possible to save part of the costly KF when the
2,3,4,5-tetrachlorobenzoyl chloride is previously fluorinated with
hydrofluoric acid, and the 2,3,4,5-tetrachlorobenzoyl fluoride, which
results in virtually quantitative yield from this reaction, is used for
the Cl/F exchange reaction with KF. Because of the greater activation by
the more electronegative fluorocarbonyl group, its greater thermal
stability, and the reduced load of KCl in the reaction mixture, this
two-stage fluorination leads to an overall improvement in the balance of
the nuclear fluorination.
The solvents which can be used for the nuclear fluorination are the inert
solvents known for fluorination reactions, for example dimethylformamide,
dimethyl sulphoxide, N-methylpyrrolidone, diethyl sulphone etc. However,
tetramethylene sulphone (sulpholane) is particularly preferably used.
The reaction temperature is between 160.degree. and 260.degree. C.,
depending on the desired degree of fluorination. While product containing
no fluorine in the nucleus is still found at the lower temperature, a very
evident proportion of the known 2,3,4,5-tetrafluorobenzoyl fluoride is
already produced at the higher temperatures (see German Patent Application
P 33 18 145, corresponding to U.S. application Ser. No. 603,480 filed Apr.
24, 1984, now pending).
Because of the thermal instability of the tetrahalogenobenzoyl halides
present in the reaction mixture--preferential formation of
octahalogenobenzophenones--it has proved to be advantageous to remove the
desired reaction product continuously from the reaction space by
distillation during the fluorination reaction. This is advantageously
carried out via a fractionating column, continuously adjusting the
distillation pressure to the partial pressure of the fluorination mixture.
It has also been found that 2,4,5-trifluoro-3-chlorobenzoyl chloride can be
obtained by reacting 2,4,5-trifluorobenzoyl chloride to give
2,4,5-trifluoro-3-chlorobenzoic acid and reacting the latter with thionyl
chloride. The 2,4,5-trifluorobenzoic acid required as starting material
for this has already been disclosed [J. I. de Graw, M. Cory, W. A.
Skinner, J. Chem. Eng. Data 13, 587 (1968)]. Its preparation according to
this literature citation is carried out, in very poor yield, from
2-amino-4,5-difluorobenzoic esters by NH.sub.2 /F exchange in the manner
of a Balz-Schiemann reaction. However, 2,4-dichloro-5-fluorobenzoyl
chloride has been disclosed in DE-OS (German Published Specification)
3,142,856=U.S. Pat. No. 4,439,620. It has now also been found that from
this, by fluorination with KF in a solvent, preferably tetramethylene
sulphone, at temperatures from 180.degree. to 230.degree. C., the new
2,4,5-trifluorobenzoyl fluoride is obtained in a straightforward manner
and in good yield, and the latter is converted virtually quantitatively
into 2,4,5-trifluorobenzoic acid by alkaline hydrolysis.
the chlorination of the 2,4,5-trifluorobenzoic acid is carried out in the
melt, under pressure and/or in a solvent, for example chlorosulphonic acid
or oleum, in the presence of halogen transfer agents, for example iodine.
2,4,5-Trifluoro-3-chlorobenzoic acid is obtained in this reaction.
However, since the reaction mixture still contains unchanged starting
material and some 2,4,5-trifluoro-3,6-dichlorobenzoic acid, the crude
mixture is treated, without intermediate isolation, with thionyl chloride.
The desired 2,4,5-rifluoro-3-chlorobenzoyl chloride is then obtained by
fractional distillation. However, it is more favorable to carry out the
separation by distillation of the acid fluorides.
the functionalization of the nitriles to give the corresponding acid
halides is carried out by, for example, hydrolysis to the carbonxylic acid
and conversion into acid chlorides using thionyl chloride. The acid
fluorides are then obtained from the acid chlorides by reaction with
fluorinating agents, for example anhydrous hydrofluoric acid or alkali
metal fluorides. Conversely, if it is desired to prepare the acid chloride
from an acid fluoride, then this is carried out by reaction with
SiCl.sub.4, where appropriate in the presence of catalytic quantities of
aluminum chloride. Halogen-substituted benzyl alcohols can be prepared in
a smooth reaction from the acid halides, especially well from the acid
fluorides, by reduction with sodium borohydride.
From the halogenated benzyl alcohols, using thionyl chloride the
corresponding benzyl chlorides are obtained in virtually quantitative
yield, and the latter can undergo further stepwise chlorination with
gaseous chlorine to give the corresponding benzal chlorides and
benzotrichlorides.
The halogenated benzaldehydes are obtained by, preferably acid, hydrolysis
of the halogenated benzal chlorides, while corresponding hydrolysis of the
halogenated benzotrichlorides provides both the corresponding acid
chlorides and the acids.
The compounds according to the invention are intended for use as starting
materials for the synthesis of medicaments.
The compounds according to the invention can be converted, for example,
into highly active antibacterial
1-cyclopropyl-6,8-dihalogeno-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoli
necarboxylic acids. The synthesis can be carried out by, for example, the
following scheme, using 5-chloro-2,3,4-trifluorobenzoyl fluoride as the
starting material.
##STR5##
More precisely and in detail the compounds obtainable by conversion of the
compounds according to the present invention are described in the
following.
The compounds which are not subject matter of the present invention are new
7-amino-1-cyclopropyl-6,8-dihalogeno-1,4-dihydro-4-oxo-3-quinolinecarboxyl
ic acids of the formula (I').
##STR6##
in which X.sup.1 and X.sup.2, which can be identical or different,
represent chlorine or fluorine, but cannot both be fluorine, and
R.sup.3 and R.sup.4, together with the nitrogen atom to which they are
bonded, form a 5- or 6-membered heterocyclic ring which can contain in
addition, as ring member, the atoms or groups, --O--, --S--, --SO--,
--SO.sub.2 --, >N--R.sup.5 or
##STR7##
and which can optionally be substituted on the carbon atoms once to three
times by C.sub.1 -C.sub.4 -alkyl, phenyl or cyclohexyl, each of which is
optionally substituted once to three times by chlorine, fluorine, bromine,
methyl, phenyl, hydroxy, methoxy, benzyloxy, nitro or piperidino,
2-thienyl, hydroxyl, alkoxy having 1 to 3 carbon atoms, amino, methylamino
or ethylamino,
R.sup.5 representing hydrogen, a branched or unbranched alkyl, alkenyl or
alkinyl group having 1 to 6 carbon atoms which can optionally be
substituted by one or two hydroxyl, alkoxy, alkylamino or dialkylamino
groups having 1 to 3 carbon atoms for an alkyl radical, the cyano group,
or the alkoxycarbonyl group having 1 to 4 carbon atoms in the alcohol
moiety, a phenylalkyl group which is optionally substituted in the phenyl
radical and has up to 4 carbon atoms in the aliphatic moiety, a phenacyl
radical which is optionally substituted once or twice by hydroxyl,
methoxy, chlorine or fluorine, or an oxoalkyl radical having up to 6
carbon atoms, furthermore denoting a radical COR.sup.6, CN or SO.sub.2
R.sup.7,
R.sup.6 representing hydrogen, straight-chain or branched alkyl which has 1
to 4 carbon atoms and is optionally substituted by 1 or 2 substituents
from the group comprising amino, alkoxycarbonyl having 1 to 3 carbon atoms
in the alkyl moiety, carboxyl or alkoxy having 1 to 3 carbon atoms, or
halogen such as chlorine, bromine or fluorine, or representing alkoxy
having 1 to 4 carbon atoms, amino, alkylamino or dialkylamino having 1 to
5 carbon atoms in the alkyl moiety, and
R.sup.7 representing straight-chain or branched alkyl having 1 to 3 carbon
atoms,
and their pharmaceutically utilisable hydrates, acid addition salts, alkali
metal, alkaline earth metal and guanidinium salts, which have high
antibacterial activity.
They are suitable as active compounds for human and veterinary medicine,
veterinary medicine also including treatment of fish for the therapy or
prevention of bacterial infections.
Preferred compounds of the formula (I') are those in which
X.sup.1 and X.sup.2, which can be identical or different, represent
chlorine or fluorine, but cannot both be fluorine, and
R.sup.3 and R.sup.4, together with the nitrogen atom to which they are
bonded, can form a 5- or 6-membered heterocyclic ring which can contain in
addition, as ring member, the atoms or groups --O--, --S--, --SO.sub.2 --,
N--R.sup.3 or
##STR8##
and which can optionally be substituted on the carbon atoms once to twice
by C.sub.1 -C.sub.3 -alkyl, cyclohexyl, phenyl which is optionally
substituted once or twice by chlorine, fluorine, bromine, methyl, phenyl,
hydroxyl, methoxy, benzyloxy, nitro or piperidino, 2-thienyl, hydroxyl,
amino or methylamino,
R.sup.5 representing hydrogen, a branched or unbranched alkyl, alkenyl or
alkinyl group having 1 to 4 carbon atoms, which can optionally be
substituted by one or two hydroxyl groups, or a phenacyl radical, an
oxoalkyl radical having up to 5 carbon atoms, and representing a radical
COR.sup.6,
R.sup.6 denoting hydrogen, straight-chain or branched alkyl having 1 to 3
carbon atoms, alkoxy having 1 to 3 carbon atoms, amino, alkylamino or
dialkylamino having 1 to 3 carbon atoms in the alkyl moiety.
Particularly preferred compounds of the formula (I') are those
in which
X.sup.1 and X.sup.2, which can be identical or different, represent
chlorine or fluorine, but cannot both be fluorine, and
R.sup.3 and R.sup.4, together with the nitrogen atom to which they are
bonded, can form a 5- or 6-membered heterocyclic ring which can contain in
addition, as ring member, an oxygen atom or the groups N--R.sup.5 or
##STR9##
and which can optionally be substituted on the carbon atoms once to twice
by C.sub.1 -C.sub.2 -alkyl, cyclohexyl, phenyl which is optionally
substituted by chlorine, fluorine, methyl, phenyl, hydroxyl, methoxy,
benzyloxy, nitro or piperidino, 2-thienyl or hydroxyl,
R.sup.5 representing hydrogen, a branched or unbranched alkyl group having
1 to 3 carbon atoms which can optionally be substituted by one or two
hydroxyl groups, or a phenacyl radical, an oxoalkyl radical having up to 4
carbon atoms and a radical COR.sup.6,
R.sup.6 denoting hydrogen or alkyl having one or two carbon atoms.
It has also been found that the compounds of the formula (I') are obtained
when the 1-cyclopropyl-7-halogeno-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acids of the formula (II')
##STR10##
in which X.sup.1 and X.sup.2 have the abovementioned meaning, and
X.sup.3 represents halogen, preferably chlorine or fluorine, are reacted
with amines of the formula (III)
##STR11##
in which R.sup.3 and R.sup.4 have the abovementioned meaning, where
appropriate in the presence of acid-binding agents (method A).
Compounds of the formula (I'), can also be obtained by reacting a
7-(1-piperazinyl)-3-quinolonecarboxylic acid of the formula (IV)
##STR12##
in which X.sup.1 and X.sup.2 have the abovementioned meaning, and the
piperazinyl radical can be substituted on the carbon atoms 1-3 times by
C.sub.1 -C.sub.4 -alkyl, 2-thienyl or optionally substituted cyclohexyl or
phenyl, with compounds of the formula (V)
R.sup.5 X (V)
in which
R.sup.5 has the abovementioned meaning but cannot be hydrogen, and
X denotes fluorine, chlorine, bromine, iodine, hydroxyl, acyloxy, ethoxy,
phenoxy or 4-nitrophenoxy,
where appropriate in the presence of acid-binding agents (method B).
Compounds of the formula (I'), are also obtained when
7-(1-piperazinyl)-3-quinolonecarboxylic acid of the formula (IV), in which
the piperazinyl radical can be substituted on the carbon atoms 1-3 times
by C.sub.1 -C.sub.4 -alkyl, 2-thienyl or optionally substituted cyclohexyl
or phenyl, is reacted with Michael acceptors of the formula (VI)
B--CH.dbd.CH.sub.2 (VI)
in which
B represents CN, CO--R.sup.8 or COOR.sup.9,
R.sup.8 representing methyl or ethyl, and
R.sup.9 representing methyl, ethyl, n- or i-propyl, (method C).
When, in the reaction by method A, 2-methylpiperazine and
6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyli
c acid are used as starting materials, then the course of the reaction can
be represented by the equation below:
##STR13##
When, in the reaction by method B, ethyl iodide and
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quin
olinecarboxylic acid are used as starting materials, then the course of the
reaction can be represented by the equation below:
##STR14##
When, for example in the reaction of (IV) with (V) by method B,
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-o
xo-3-quinolinecarboxylic acid and formic acetic anhydride are used as
starting compounds, then the course of the reaction can be represented by
the equation below:
##STR15##
When, for example by method C,
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quin
olinecarboxylic acid and methyl vinyl ketone are used as starting
compounds, then the course of the reaction can be represented by the
equation below:
##STR16##
The 1-cyclopropyl-6,7,8-trihalogeno-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acids of the formula (II') which can be used as starting materials by
method A can be prepared in accordance with the following reaction scheme:
##STR17##
According to this, diethyl malonate (2) is acylated with the appropriate
benzoyl fluoride or chloride (1), in the presence of magnesium ethylate,
to give the aroylmalonic ester (3) (Organicum, 3rd edition, 1964, page
438).
By partial hydrolysis and decarboxylation of (3) in aqueous medium using
catalytic amounts of sulphuric acid or p-toluenesulphonic acid, the ethyl
aroylacetates (4) are obtained in good yield, and these are converted with
triethyl orthoformate/acetic anhydride into ethyl
2-(2,3,4,5-tetrahalogenobenzoyl)-3-ethoxyacrylates (5). The reaction of
(5) with cyclopropylamine in a solvent such as, for example, methylene
chloride, alcohol, chloroform, cyclohexane or toluene leads, in a slightly
exothermic reaction, to the desired intermediate (6).
The cyclisation reaction (6).fwdarw.(7) is carried out in a temperature
range of about 60.degree. to 300.degree. C., preferably 80.degree. to
180.degree. C.
The diluents which can be used are dioxane, dimethyl sulphoxide,
N-methylpyrrolidone, sulpholane, hexamethylphosphoric trisamide and,
preferably, N,N-dimethylformamide.
Suitable acid-binding agents for this reaction step are potassium
tert.-butanolate, butyllithium, lithiumphenyl, phenyl magnesium bromide,
sodium methylate, sodium hydride, sodium or potassium carbonate and,
particularly preferably, potassium or sodium fluoride. It can be
advantageous to use an excess of 10 mol-% of base.
The ester hydrolysis of (7) carried out in the last step under basic or
acid conditions leads to the
1-cyclopropyl-6,7,8-trihalogen-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acids (II').
The benzoyl halides (1) used as starting materials for this synthetic route
are prepared as follows: 3,5-dichloro-2,4-difluorobenzoyl fluoride
(boiling point 97.degree./20 mbar; n.sub.D.sup.20 =1.5148) and
5-chloro-2,3,4-trifluorobenzoyl fluoride (boiling point
(68.degree.-70.degree./20 mbar; n.sub.D.sup.20 =1.4764) are obtained
together by heating tetrachlorobenzoyl chloride with potassium fluoride in
sulpholane at elevated temperatures:
##STR18##
The chlorination of 2,4,5-trifluorobenzoic acid in chlorosulphonic acid
leads to 3-chloro-2,4,5-trifluorobenzoic acid which is reacted as the
crude product with thionyl chloride to give
3-chloro-2,4,5-trifluorobenzoyl chloride (boiling point 94.degree./18
mbar; n.sub.D.sup.20 =1.5164):
##STR19##
The amines (III) used as starting materials are known or can be obtained by
processes known from the literature [U.S. Pat. No. 4,166,180, J. Med.
Chem. 26, 1116 (1983). From the 2-arylpiperazines, the corresponding
2-cyclohexylpiperazines are obtained by catalytic hydrogenation; for
example: 2-cyclohexylpiperazine (waxlike, melting point
71.degree.-73.degree. C.). Examples which may be mentioned are:
morpholine, piperidine, thiomorpholine, pyrrolidine, piperazine,
N-methylpiperazine, N-ethylpiperazine, N-(2-hydroxyethyl)piperazine,
N-formylpiperazine, 2-methylpiperazine, 1,2-dimethylpiperazine, cis- and
trans-2,5-dimethylpiperazine, cis- and trans-2,6-dimethylpiperazine,
2-ethylpiperazine, 2-propylpiperazine, 2-isopropylpiperazine,
2-isobutylpiperazine, 2-piperazinone, 1-methyl-2-piperazinone,
1-ethyl-2-piperazinone, 2-cyclohexylpiperazine, 2-phenylpiperazine,
2-(4-chlorophenyl)piperazine, 2-(4-fluorophenyl)piperazine,
2-(4-bromophenyl)piperazine, 2-(4-methylphenyl)piperazine,
2-(4-biphenylyl)-piperazine. 2-(4-methoxyphenyl)piperazine,
2-(4-benzyloxyphenyl)piperazine, 2-(4-hydroxyphenyl)piperazine,
2-(4-nitrophenyl)piperazine, 2-(3-nitrophenyl)piperazine,
2-(4-piperidinophenyl)piperazine, 2-(3,4-dimethoxyphenyl)piperazine,
2-(3,4,5-trimethoxyphenyl)piperazine,
2-(3,4-dimethoxy-6-methyl)piperazine, 2-(2-thienyl)piperazine and
3-aminopyrrolidine.
The compounds of the formula (V) which are used as starting materials are
known. Examples which may be mentioned are: methyl iodide, methyl bromide,
ethyl iodide, ethyl bromide, ethyl chloride, 2-hydroxyethyl chloride,
3-hydroxypropyl chloride, 4-hydroxybutyl chloride, n-propyl bromide,
i-propyl iodide, n-butyl bromide, i-butyl bromide, sec.-butyl chloride,
n-pentyl chloride, 3-methylbutyl chloride and n-hexyl bromide, formic
acetic anhydride, acetic anhydride, propionic anhydride, acetyl chloride,
chloroacetyl chloride, onic anhydride, acetyl chloride, chloroacetyl
chloride, dichloroacetyl chloride, bromoacetyl bromide, butyryl chloride,
4-chlorobutyryl chloride, isobutyryl chloride, 4-nitrophenyl ester of
N-(tert.-butoxycarbonyl)-glycine, 4-nitrophenyl ester of
N-(tert.-butoxycarbonyl)-L-alanine, 4-nitrophenyl ester of
N-(tert.-butoxycarbonyl)-L-leucine, 4-nitrophenyl ester of
N-(tert.-butoxycarbonyl)-L-valine, 3-methoxypropionyl chloride, methyl
chlorocarbonate, ethyl chlorocarbonate, n-butyl chlorocarbonate, diethyl
carbonate, cyanogen chloride, diphenyl carbonate, cyanogen bromide,
dimethylcarbamoyl chloride, methanesulphonyl chloride, ethanesulphonyl
chloride, propane-1-sulphonyl chloride and formic acid.
The compounds of the formula (VII) which can be used according to the
invention are known. Examples which may be mentioned are: acrylonitrile,
methyl vinyl ketone, methyl acrylate and ethyl acrylate.
The reaction of (II') with (III) by method A is preferably carried out in a
diluent such as dimethyl sulphoxide, N,N-dimethylformamide,
hexamethylphosphoric trisamide, sulpholane, water, an alcohol, such as
methanol, ethanol, n-propanol, isopropanol or glycol monomethyl ether, or
pyridine. It is equally possible to use mixtures of these solvents.
All customary inorganic and organic acid-binding agents can be used as the
acid-binding agent. These preferably include the alkali metal hydroxides,
alkali metal carbonates, organic amides and amidines. The following may be
specifically mentioned as being particularly suitable: triethylamine,
1,4-diazabicyclo[2.2.2]octaine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) or excess amine (III).
The reaction temperatures can be varied within a relatively wide range. In
general, the process is carried out between about 20.degree. and
200.degree. C. preferably between 80.degree. and 180.degree. C.
The reaction can be carried out under atmospheric pressure as well as under
elevated pressure. In general, it is carried out under pressures between
about 1 and about 100 bar, preferably between 1 and 10 bar.
When carrying out the process according to the invention, 1 to 15 moles,
preferably 1 to 6 moles, of the amine (III) are used for 1 mole of
carboxylic acid (II').
The reaction of (IV) with (V) is preferably carried out in a diluent such
as dimethyl sulphoxide, dioxane, N,N-dimethylformamide,
hexamethylphosphoric trisamide, sulpholane, water, an alcohol, such as
methanol, ethanol, n-propanol, isopropanol or glycol monomethyl ether, or
pyridine. It is equally possible to use mixtures of these diluents.
All customary inorganic and organic acid-binding agents can be used as the
acid-binding agent. These preferably include the alkali metal hydroxides,
alkali metal carbonates, organic amines and amidines. The following may be
specifically mentioned as being particularly suitable: triethylamine,
1,4-diazabicyclo[2.2.2]octane (DABCO) or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The reaction temperatures can be varied within a relatively wide range. In
general, the process is carried out between about 20.degree. and about
180.degree. C., preferably between 40.degree. and 110.degree. C.
The reaction can be carried out under atmospheric pressure as well as under
elevated pressure. In general, it is carried out under pressures between
about 1 and about 100 bar, preferably between 1 and 10 bar.
When carrying out the process according to the invention by method B, 1 to
4 moles, preferably 1 to 1.5 mole, of the compound (V) is used for 1 mole
of the compound (IV).
The reaction of (IV) with (VI) (method C) is preferably carried out in a
diluent such as dioxane, dimethyl sulphoxide, N,N-dimethylformamide,
methanol, ethanol, isopropranol, n-propanol or glycol monomethyl ether or
in mixtures of these diluents.
The reaction temperatures can be varied within a relatively wide range. In
general, the process is carried out between about 20.degree. C. and about
150.degree. C., preferably between 50.degree. C. and 100.degree. C.
The reaction can be carried out under atmospheric pressure as well as under
elevated pressure. In general, it is carried out under pressures between
about 1 and about 100 bar, preferably between 1 and 10 bar.
When carrying out the process according to the invention by method C, 1 to
5 moles, preferably 1 to 2 moles, of the compound (VI) are used for 1 mole
of the compound (IV).
Apart from the compounds listed in the examples, the following may be
specifically mentioned as active compounds obtainable from the compounds
of the invention:
6-chloro-7-[3-(4-chlorophenyl)-1-piperazinyl]-1-cyclopropyl-8-fluoro-1,4-d
ihydro-4-oxo-3-quinolinecarboxylic acid,
6-chloro-1-cyclopropyl-8-fluoro-7-[3-(4-fluorophenyl)-1-piperazinyl]-1,4-d
ihydro-4-oxo-3-quinolinecarboxylic acid,
7-[3-(4-bromophenyl)-1-piperazinyl]-6-chloro-1-cyclopropyl-8-fluoro-1,4-di
hydro-4-oxo-3-quinolinecarboxylic acid,
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-methylphenyl)-1-pipera
zinyl]-4-oxo-3-quinolinecarboxylic acid,
7-[3-(4-biphenylyl)-1-piperazinyl]-6-chloro-1-cyclopropyl-8-fluoro-1,4-dih
ydro-4-oxo-3-quinolinecarboxylic acid,
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-methoxyphenyl)-1-piper
azinyl]-4-oxo-3-quinolinecarboxylic acid,
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-hydroxyphenyl)-1-piper
azinyl]-4-oxo-3-quinolinecarboxylic acid,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperaziny
l)-3-quinolinecarboxylic acid,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[(4-nitrophenyl)-1-pip
erazinyl]-3-quinolinecarboxylic acid,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(4-piperidino-pheny
l)-1-piperazinyl]-3-quinolinecarboxylic acid,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3,4-dimethoxy-phen
yl)-1-piperazinyl]-3-quinolinecarboxylic acid,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3,4,5-trimethoxy-p
henyl)-1-piperazinyl]-3-quinolinecarboxylic acid,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(2-thienyl)-1-piper
azinyl]-3-quinolinecarboxylic acid,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperidino-3-quinoline
carboxylic acid,
7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-o
xo-3-quinolinecarboxylic acid,
6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline
carboxylic acid,
7-(4-acetyl-1-piperazinyl)-6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid,
7-(4-acetyl-1-piperazinyl)-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-o
xo-3-quinolinecarboxylic acid,
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-
4-oxo-3-quinolinecarboxylic acid,
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-morpholino-3-quinoline
carboxylic acid,
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-3-quino
linecarboxylic acid and
8-chloro-1-cyclopropyl-7-(4-ethyl-3-oxo-1-piperazinyl)-6-fluoro-1,4-dihydr
o-4-oxo-3-quinolinecarboxylic acid.
The examples which follow shall illustrate end products obtainable from
compounds which are subject matter of the present invention.
EXAMPLE A
6-Chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid
##STR20##
15.7 g (0.65 mole) of magnesium turnings are stirred in 40 ml of ethanol
and 2 ml of tetrachloromethane and, after the reaction has started, 103 g
(0.64 mole) of diethyl malonate in 80 ml of ethanol and 250 ml of toluene
are added dropwise at 50.degree.-60.degree.. The mixture is stirred at
this temperature for 1 hour, cooled to -5.degree. to -10.degree., a
solution of 138 g (0.65 mole) of 5-chloro-2,3,4-trifluoro-benzoyl fluoride
in 63 ml of toluene is added dropwise, and the mixture is stirred further
at 0.degree. for 1 hour and allowed to stand overnight at room
temperature. It is then heated at 40.degree.-50.degree. for 2 hours,
cooled, and 250 ml of ice-water and 38.5 ml of concentrated sulphuric acid
are added. The organic phase is separated off, the aqueous phase is
extracted with 2.times.150 ml of toluene, and the combined organic phases
are washed with saturated sodium chloride solution, dried with sodium
sulphate and concentrated.
200 ml of water are added to the residue (it is advantageous to add 0.4 g
of 4-toluenesulphonic acid at this point) and the mixture is heated under
reflux for 5 hours for the deethoxycarbonylation. The mixture is extracted
with 3.times.200 ml of dichloromethane, and the extracts are washed with
saturated sodium chloride solution, dried with sodium sulphate,
concentrated and distilled under high vacuum. 103 g (56.5%) of ethyl
(5-chloro-2,3,4-trifluorobenzoyl)-acetate with a boiling point of
110.degree./0.9 Torr are obtained.
103 g (0.37 mole) of the ester obtained and 83 g (0.56 mole) of triethyl
orthoformate are heated with 95 g of acetic anhydride at
150.degree.-160.degree. for 2 hours and then concentrated at
120.degree.-130.degree. under atmospheric pressure and thereafter under
high vacuum. 115 g (92% of theory) of ethyl
(2-(5-chloro-2,3,4-trifluorobenzoyl)-3-ethoxyacrylate are obtained as an
oil.
14.8 g (0.26 mole of cycloproplamine are added dropwise to 84.1 g (0.25
mole) of this compound in 170 ml of ethanol, cooling in ice, and the
mixture is stirred at room temperature for 2 hours. It is then stirred
with 170 ml of water, cooled in ice, and the precipitate which has
separated out is filtered off with suction, washed with water and a little
methanol and dried. 47 g (54%) of ethyl
2-(5-chloro-2,3,4-trifluorobenzoyl)-3-cyclopropylaminoacrylate of melting
point 71.degree.-73.degree. are obtained. The product is a cis/trans
mixture according to the .sup.1 H NMR spectrum.
47 g (0.14 mole) of this compound in 230 ml of dimethylformamide are heated
with 9.7 g (0.23 mole) of sodium fluoride at 160.degree.-170.degree. for 2
hours. The reaction mixture is poured into 400 ml of ice-water, and the
precipitate is filtered off with suction, washed with water and dried. 44
g (99% of ethyl
6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyla
te of melting point 169.degree.-172.degree. are isolated.
33 ml of concentrated sulphuric acid are added to 44 g (0.13 mole) of the
quinolonecarboxylic ester in 300 ml of glacial acetic acid and 179 ml of
water and the reaction mixture is heated at 150.degree. C. for 2 hours. It
is stirred into 400 ml of ice-water, and the precipitate is filtered off
with suction, washed with water and dried. 37 g (95% of theory) of
6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyli
c acid isolated with a melting point of 200.degree.-204.degree..
EXAMPLE B
8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid
##STR21##
3-Chloro-2,4,5-trifluorobenzoyl chloride is reacted in analogy to Example
A, the following steps being passed through: ethyl
(3-chloro-2,4,5-trifluorobenzoyl)acetate as the enol (yield: 42%, melting
point 72-75), ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate
(crude yield: 95% oil), ethyl
2-(3-chloro-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate (yield:
67%, melting point 78.degree.-80.degree.), ethyl
8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyla
te (yield: 85%, melting point 154.degree.-157.degree.),
8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyli
c acid (yield: 97.6%, melting point 189.degree.-192.degree.).
EXAMPLE C
6,8-Dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid
##STR22##
3,5-Dichloro-2,4-difluorobenzoyl fluoride is reacted in analogy to Example
A, the following steps being passed through: ethyl
(3,5-dichloro-2,4-difluorobenzoyl)acetate (yield: 43%, melting point
133.degree./2.5 Torr), ethyl
2-(3,5-dichloro-2,4-difluorobenzoyl)-3-ethoxyacrylate (crude yield: 95%
oil), ethyl 2(3,5-dichloro-2,4-difluorobenzoyl)-3-cyclopropylaminoacrylate
(yield: 96%, melting point 71.degree.-74.degree.), ethyl
6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyla
te (yield: 97%, melting point 215.degree.-217.degree. with decomposition),
6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyli
c acid (yield: 93%, melting point 204.degree.-206.degree.).
EXAMPLE 1
##STR23##
12 g (40 mmol) of the product from Example A in 100 ml of pyridine are
heated with 17.2 g (0.2 mole) of piperazine under reflux for 5 hours. The
mixture is concentrated in vacuo, the residue is stirred with 120 ml of
water and the pH is adjusted to 5 with 2N hydrochloric acid. The
precipitate is filtered off with suction, washed with water and methanol,
boiled in 80 ml of methanol and dried. 12.3 g (84% of theory)
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quin
olinecarboxylic acid of melting point 295.degree.-298.degree. (with
decomposition) are obtained.
The following
6-chloro-1-cyclopropyl-8fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acids substituted in the 7-position are obtained in analogy to Example 1:
______________________________________
##STR24##
##STR25##
##STR26##
##STR27##
______________________________________
##STR28## 258-282.degree. (decomposition)
3
##STR29## 191-195.degree. (decomposition)
4
##STR30## above.about.274.degree. (decomposition)
5
##STR31## 255-261.degree. (decomposition)
6
##STR32## >320.degree. (decomposition)
7
##STR33## 276-280.degree. (decomposition)
8
##STR34## above.about.190.degree. (decomposition)
9
##STR35## 154-158
______________________________________
EXAMPLE 10
##STR36##
1.83 g (5 mmol) of the product from Example 1 in 20 ml of dimethylformamide
are heated with 1.6 g of ethyl iodide and 1 g of triethylamine at
80.degree. for 3 hours. The reaction mixture is concentrated in vacuo, and
the residue is stirred with 20 ml of water and recrystallised from
methanol. 0.4 g (15% of theory) of
6-chloro-1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-8-fluoro-1,4-dihydro-4-ox
o-3-quinolinecarboxylic acid of melting point 237.degree.-242.degree. (with
decomposition) is obtained.
EXAMPLE 11
##STR37##
3.65 g (0.01 mmol) of the product from Example 1 are suspended in 150 ml of
ethanol and 30 ml of water, the suspension is adjusted to pH 4.6 with
acetic acid, and then, at room temperature, 3.4 g (0.02 mol) of
2,3-cyclohexylideneglyceraldehyde and, in portions, 950 mg of sodium
cyanoborohydride are added. The mixture is stirred at room temperature
overnight, the pH is adjusted to 8 with sodium bicarbonate, extraction
with dichloromethane is carried out, and the extract is concentrated. 3 ml
of concentrated hydrochloric acid are added to the residue in 25 ml of
ethanol and 25 ml of water, and the mixture is heated under reflux for 6
hours. It is concentrated, the residue is dissolved in water, the solution
is extracted with dichloromethane, concentration is again carried out, and
the residue is stirred with ethanol and dried. 1.3 g of
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[4-(2,3-dihydroxypropyl)-1-p
iperazinyl]-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point
263.degree.-266.degree. (with decomposition) is obtained.
EXAMPLE 12
##STR38##
1.83 g (5 mmol) of the product from Example 1 and 1.95 g (28 mmol) of
methyl vinyl ketone in 25 ml of ethanol are heated under reflux for 6
hours, and the precipitate is filtered off with suction and recrystallised
from glycol monomethyl ether. 1 g (46% of theory) of
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-[4-(3-oxobutyl)-1-pipe
razinyl]-3-quinolinecarboxylic acid of melting point
187.degree.-190.degree. (with decomposition) is obtained.
EXAMPLE 13
##STR39##
1.83 g (5 mmol) of the product from Example 1 in 25 ml of ethanol are
heated with 1.95 g (20 mmol) of chloroacetone under reflux for 6 hours.
The suspension is cooled, and the precipitate is filtered off with
suction, thoroughly washed with ethanol and dried in vacuo, 1 g (44% of
theory) of
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-[4-(2-oxopropyl)-1-pip
erazinyl]-3-quinolinecarboxylic acid hydrochloride of melting point
.about.320.degree. C. (with decomposition) being obtained.
EXAMPLE 14
##STR40##
3.66 g (0.01 mole) of the product from Example 1 in 50 ml of
dimethylformamide are heated with 2.2 g of .omega.-chloroacetophenone and
2.2 g of triethylamine at 60.degree. for 10 hours. The reaction mixture is
concentrated in vacuo, the residue is stirred with 30 ml of water, and the
precipitate is filtered off with suction, washed with water and
recrystallised from acetone. 1.2 g (25% of theory) of
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-[4-(2-oxo-2-phenylethy
l)-1-piperazinyl]-3-quinolinecarboxylic acid of melting point
175.degree.-179.degree. (with decomposition) is obtained.
EXAMPLE 15
##STR41##
1.5 g (4 mmol) of the product from Example 1 are dissolved in a mixture of
10 ml of dioxane and 170 mg of sodium hydroxide in 2.5 ml of water and
then, simultaneously, a solution of 0.7 g of formic acetic anhydride in 5
ml of dioxane and a solution of 340 mg of sodium hydroxide in 5 ml of
water are added. The mixture is stirred at room temperature for 2 hours,
diluted with 30 ml of water, and the precipitate is filtered off with
suction, washed with water and methanol and recrystallised from glycol
monomethyl ether. 0.6 g (38%) of
6-chloro-1-cyclopropyl-8-fluoro-7(4-formyl-1-piperazinyl)-1,4-dihydro-4-ox
o-3quinolinecarboxylic acid of melting point 277.degree.-278.degree. (with
decomposition) is obtained.
EXAMPLE 16
##STR42##
When the product from Example 2 is reacted in analogy to Example 15, then
6-chloro-1-cyclopropyl-8-fluoro-7(4-formyl-3-methyl-1-piperazinyl)-1,4-dih
ydro-4-oxo-3-quinolinecarboxylic acid of melting point
280.degree.-282.degree. (with decomposition) is obtained.
EXAMPLE 17
##STR43##
3 g (10 mmol) of the product from Example A in 35 ml of dimethyl sulphoxide
are heated at 140.degree. with 1.2 g (10 mmol) of 2,6-dimethylmorpholine
and 2.2 g (20 mmol) of diazabicyclo[2.2.2]octane for 5 hours. The mixture
is concentrated under high vacuum, stirred with 30 ml of water, the pH is
adjusted to 6 with 2N hydrochloric acid, and the precipitate is filtered
off with suction and recrystallised from glycol monomethyl ether. 1.6 g
(41% of theory) of
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(2.6-dimethyl-4-morpholinyl)
-4-oxo-3-quinolinecarboxylic acid of melting point 258.degree.-261.degree.
(with decomposition) is obtained.
EXAMPLE 18
##STR44##
When the product from Example A is reacted with 4-hydroxypiperidine in
analogy to Example 17, then
6-chloro-1-cyclopropyl-8-1,4-dihydro-7-(4-hydroxy-1-piperidinyl)-4-oxo-3-q
uinolinecarboxylic acid of melting point 226.degree.-231.degree. (with
decomposition) is obtained.
EXAMPLE 19
##STR45##
3 g (0.01 mole) of the product from Example B in 25 ml of pyridine are
heated with 4 g (0.04 mole) of 1-methylpiperazine under reflux for 5
hours. The mixture is concentrated in vacuo, 20 ml of water are added, the
pH is adjusted to 5 with 2N hydrochloric acid, and the precipitate which
has separated out is recrystallised from methanol. 0.6 g (16% of theory)
of 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-
4-oxo-3-quinolinecarboxylic acid of melting point 293.degree.-297.degree.
(with decomposition) is obtained.
EXAMPLE 20
##STR46##
In analogy to Example 19, with 2-methylpiperazine,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-o
xo-3-quinolinecarboxylic acid of melting point 318.degree.-325.degree.
(with decomposition) is obtained.
EXAMPLE 21
##STR47##
In analogy to Example 19, the product from Example B is reacted with
piperazine under reflux for 1.5 hours, and the reaction mixture is treated
with hydrochloric acid,
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-3-quinolinec
arboxylic acid hydrochloride with a decomposition point above 330.degree.
being obtained.
EXAMPLE 22
##STR48##
When the product from Example C is reacted with 2-methylpiperazine in
analogy to Example 19, then
6,8-dichloro-1-cyclopropyl-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-
quinolinecarboxylic acid of melting point 288.degree.-291.degree. (with
decomposition) is obtained.
EXAMPLE 23
##STR49##
3.2 g (0.01 mole) of the product from Example C are heated with 4 g (0.04
mole) of 1-methylpiperazine at 80.degree. for 3 days, the reaction mixture
is concentrated in vacuo, and the residue is taken up in a little water
and the pH is adjusted to 7 with 2N hydrochloric acid. Crystallisation
takes place on standing in ice. The precipitate was filtered off with
suction and recrystallised from water with the addition of a little
hydrochloric acid. 0.6 g
6,8-dichloro-1-cyclopropyl-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-
quinolinecarboxylic acid of melting point >300.degree. is obtained.
EXAMPLE 24
##STR50##
3 g (10 mmol) of the product from Example 1 in 25 ml of dimethyl sulphoxide
are heated with 1.8 g (18 mmol) of 2-piperazinone and 2.2 g (20 mmol) of
diazabicyclo[2.2.2]octane at 130.degree. for 2 hours. The suspension is
adjusted to pH 5 with 2N hydrochloric acid, 25 ml of water area added, and
the precipitate is filtered off with suction, extracted by boiling with 20
ml of methanol and dried. 1.5 g (39% of theory) of
6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-
3-quinolinecarboxylic acid of melting point 288.degree.-291.degree. (with
decomposition) is obtained.
Examples following are examples of compounds according to the present
invention:
EXAMPLE 25
2,4,5-Trifluorobenzoyl fluoride
By treating 2,4-dichloro-5-fluorobenzoylchloride (b.p. 113/14 mbar,
n.sub.D.sup.20 : 1.5722) with a 4-fold excess of anhydrous HF at
120.degree. in an autoclave for 3 hours with the elimination of hydrogen
chloride, 2,4-dichloro-5-fluoro-benzoyl fluoride with a boiling point of
98.degree. C./15 mbar, n.sub.D.sup.20 : 1.5355, is prepared.
878 g of 2,4-dichloro-5-fluorobenzoyl fluoride are reacted, in 2,350 ml of
tetramethylene sulphone in a three-necked flask with stirrer, thermometer
and a distillation column, with 1,142 g of anhydrous KF at 200.degree. C.
for 3.5 hours. During this, distillate is continuously removed through the
distillation column, initially at 750 mbar, and towards the end at about
80 mbar. The crude distillate is subjected to fractional redistillation.
486 g (65.5% of theory) of 2,4,5-trifluorobenzoyl fluoride, of boiling
point 52.degree.-3.degree./20 mbar, n.sub.D.sup.20 : 1.4530, are obtained.
After hydrolysis of 161 g of 2,4,5-trifluorobenzoyl fluoride with a
solution of 100 g of sodium hydroxide in 1 l of water at 40.degree.
(exothermic up to 70.degree.), diluting the mixture with 1 l of water,
acidifying the diluted mixture with hydrochloric acid filtering the
acidified mixture and drying the product 2,4,5-trifluorobenzoic acid with
a melting point of 95.degree. C. is obtained in an almost quantitative
yield.
EXAMPLE 26
Fluorination of 2,3,4,5-tetrachlorobenzoyl chloride
2,749 g of 2,3,4,5-tetrachlorobenzoyl fluoride, of melting point
52.degree.-53.degree. C., are obtained from 2,994 g of
2,3,4,5-tetrachlorobenzoyl chloride, of boiling point 118.degree. C./0.5
mbar, melting point 38.degree. C., after fluorination with 1.6 l of
anhydrous hydrofluoric acid in 2.0 l of methylene chloride at 60.degree.
C. in an autoclave (5 hours), and after distillation of the HF and the
solvent.
This quantity is heated together with 2,914 g of anhydrous KF in 7,250 ml
of tetramethylene sulphone in a three-necked flask, and initially about
500 ml of the solvent is distilled out again to remove any residual water.
The reaction mixture is then heated at 240.degree. C., with vigorous
stirring, for about 4.5 hours. During this, the initial pressure of 800
mbar is reduced continuously to 500 mbar. At the same time, the mixture of
fluorination products is removed as the distillate through the
fractionating column. The total obtained is 1,840 g. The following are
obtained from this by fractional redistillation:
206 g of 2,3,4,5-tetrafluorobenzoyl fluoride, boiling point:
45.degree.-7.degree. C./20 mbar, n.sub.D.sup.20 : 1.4372;
954 g of 5-chloro-2,3,4-trifluorobenzoyl fluoride, boiling point:
68.degree.-70.degree. C./20 mbar, n.sub.D.sup.20 : 1.4764;
330 g of 3,5-dichloro-2,4-difluorobenzoyl fluoride, boiling point:
97.degree. C./20 mbar, n.sub.D.sup.20 : 1.5148.
64 g of 5-chloro-2,3,4-trifluorobenzoyl fluoride are heated with 13 g of
SiCl.sub.4 in the presence of 0.1 g of AlCl.sub.3. The reaction starts at
about 35.degree. C. and is completed at a temperature of up to about
100.degree. C., and then the residue is worked up by distillation. The
following is obtained:
62 g of 5-chloro-2,3,4-trifluorobenzoyl chloride, boiling point: 88.degree.
C./14 mbar, n.sub.D.sup.20 : 1.5146.
3,5-Dichloro-2,4-difluorobenzoyl chloride is also obtained correspondingly,
as a liquid of boiling point 113.degree.-4.degree. C./15 mbar,
n.sub.D.sup.20 : 1.5512.
When 5-chloro-2,3,4-trifluorobenzoyl fluoride is briefly treated with
aqueous sodium hydroxide solution then, after acidification and drying,
crystals of 5-chloro-2,3,4-trifluorobenzoic acid are obtained, melting
point: 123.degree.-4.degree. C.
3,5-Dichloro-2,4-difluorobenzoic acid is obtained correspondingly, melting
point: 179.degree. C.
EXAMPLE 27
5-Chloro-2,3,4-trifluorobenzyl alcohol
62 g of NaBH.sub.4 are initially introduced into 320 ml of dioxane. A
solution of 319 g of 5-chloro-2,3,4-trifluorobenzoyl fluoride in 640 ml of
dioxane is run into this, at the reflux temperature, over the course of 6
hours. After boiling under reflux for a further hour, the mixture is
poured into ice, the pH is adjusted to 1 with dilute hydrochloric acid,
and the organic phase is extracted with methylene chloride and then
distilled:
261 g of 2,3,4-trifluoro-5-chlorobenzyl alcohol of boiling point
109.degree. C./12 mbar are obtained.
3,5-Dichloro-2,4-difluorobenzyl alcohol is obtained correspondingly, as
crystals of boiling point 134.degree. C./13 mbar, melting point:
55.degree. C., from 3,5-dichloro-2,4-difluorobenzoyl fluoride.
EXAMPLE 28
3-Chloro-2,4,5-trifluorobenzoyl fluoride
150 g of 2,4,5-trifluorobenzoic acid are dissolved in 150 ml of
chlorosulfonic acid and, after addition of 3 g of iodine, chlorination is
carried out with gaseous chlorine at 50.degree. to 60.degree. C.
Chlorination is continued until about 35 to 50% of the starting material
has been converted, and then the mixture is cautiously decomposed on ice.
The mixture of nuclear halogenated acids is filtered off with suction and
dried (purification of a sample by repeated recrystallization gives a
melting point of 114.degree.-5.degree. C. for
3-chloro-2,4,5-trifluorobenzoic acid).
The crude mixture is converted into the mixture of acid chlorides using
excess thionyl chloride in the presence of a few drops of
dimethylformamide. 3-Chloro-2,4,5-trifluorobenzoyl chloride is isolated by
precision distillation of a sample, boiling point 94.degree. C./18 mbar,
n.sub.D.sup.20 : 1.5164.
100 ml of anhydrous HF are added to the remainder in a stainless steel
autoclave at about -5.degree. C. and, after the evolution of HCl has
subsided, the mixture is briefly heated to 60.degree. C. to complete the
reaction and then worked up by distillation. 38 g of
3-chloro-2,4,5-trifluorobenzoyl fluoride of boiling point 65.degree. C./18
mbar, n.sub.D.sup.20 : 1.4760 are isolated.
3-Chloro-2,4,5-trifluorobenzyl alcohol is obtained by reduction of the acid
fluoride with NaBH.sub.4 : boiling point 109.degree. C./14 mbar, melting
point 32.degree. C.
39 g of 3-chloro-2,4,5-trifluorobenzyl alcohol are oxidised in 92 ml of
acetone with a solution of 20 g of Na.sub.2 Cr.sub.2 O.sub.7 in 81 ml of
water and 14 ml of concentrated sulphuric acid for 2 hours at 20.degree.
to 25.degree. C., the organic phase is washed with aqueous sodium
carbonate solution and dried with sodium sulphate. After evaporating off
the solvent and after distillation 2,4,5-trifluoro-3-chlorobenzaldehyde,
b.p. 72.degree. C./12 mbar, n.sub.D.sup.20 : 1.5055, which crystallises
slowly and has a melting point of 31.degree.-32.degree. C., is obtained.
EXAMPLE 29
Fluorination of 2,3,4,5-tetrachlorobenzonitrile
2,3,4,5-Tetrachlorobenzonitrile of melting point: 123.degree.-5.degree. C.
(prepared from 2,3,4,5-tetrachlorobenzoyl chloride, melting point:
30.degree. C., via 2,3,4,5-tetrachlorobenzamide, melting point:
206.degree.) are fluorinated with KF in tetramethylene sulphone. The
following are isolated by fractional distillation of the fluorination
mixture:
2,3,4,5-tetrafluorobenzonitile, boiling point 50.degree. C./15 mbar,
n.sub.D.sup.20 : 1.4562;
5-chloro-2,3,4-triflurobenzonitrile, boiling point 78.degree. C./14 mbar,
n.sub.D.sup.20 1.4960; and
3,5-dichloro-2,4-difluorobenzonitrile, boiling point 113.degree. C./19
mbar, melting point: 39.degree.-40.degree. C.
EXAMPLE 30
3,5-Dichloro-2,4-difluorobenzamide
620 ml of concentrated aqueous ammonia solution and 600 ml of water are
initially introduced, 458 g (2 moles) of 3,5-dichloro-2,4-difluorobenzoyl
fluoride are added dropwise at 40.degree.-50.degree., and then the mixture
is stirred at 50.degree. for 30 minutes. The precipitate is filtered off
with suction, washed with water and dried. 408 g (90% of theory) of
3,5-dichloro-2,4-difluorobenzamide of melting point
163.degree.-164.degree. are obtained.
The following are obtained analogously:
5-chloro-2,3,4-trifluorobenzamide, melting point: 135.degree.-137.degree.,
5-chloro-2,4,5-trifluorobenzamide, melting point: 125.degree.,
2,4,5-trifluorobenzamide, melting point: 145.degree.-147.degree., and
2,3,4,5-trifluorobenzamide, melting point: 206.degree..
EXAMPLE 31
3,5-Dichloro-2,4-difluorobenzyl chloride
354 ml of thionyl chloride and 1 drop of dimethylformamide are initially
introduced at room temperature, and 375 g (1.76 mol) of
3,5-dichloro-2,4-difluorobenzyl alcohol are added dropwise. The mixture is
heated under reflux until evolution of gas has finished. The excess
thionyl chloride is removed by distillation, and the residue is distilled
in vacuo. 386 g (95% of theory) of 3,5-dichloro-2,4-difluorobenzyl
chloride of boiling point 107.degree./12 mbar, n.sub.D.sup.20 : 1.5368,
are obtained. The following are obtained analogously:
5-chloro-2,3,4-trifluorobenzyl chloride, boiling point 78.degree./13 mbar;
n.sub.D.sup.20 : 1.4972, and
3-chloro-2,4,5-trifluorobenzyl chloride, boiling point 80.degree./16 mbar;
n.sub.D.sup.20 : 1.4966.
EXAMPLE 32
Chlorination of 5-chloro-2,3-trifluorobenzyl chloride
187 g (0.87 mol) of 5-chloro-2,3,4-trifluorobenzyl chloride are initially
introduced and are chlorinated with less than the stoichiometric amount of
chlorine, at 100.degree.-105.degree. C. with UV irradiation. According to
assay by gas chromatography, the crude mixture contains 66%
5-chloro-2,3,4-trifluorobenzal chloride and 32%
5-chloro-2,3,4-trifluorobenzotrichloride. The following are obtained after
fractional distillation:
94 g (43% of theory) of 5-chloro-2,3,4-trifluorobenzal chloride, boiling
point 88.degree./12 mbar, n.sub.D.sup.20 1.5082;
33 g (13% of theory) of 5-chloro-2,3,4-trifluorobenzotrichloride, boiling
point 104.degree./12 mbar, n.sub.D.sup.20 : 1.5235.
The following are obtained analogously:
3,5-dichloro-2,4-difluorobenzal chloride, boiling point 114.degree./14
mbar, n.sub.D.sup.20 : 1.5443,
3,5-dichloro-2,4-difluorobenzotrichloride, boiling point 128.degree./14
mbar, melting point 43.degree..
EXAMPLE 33
5-Chloro-2,3,4-trifluorobenzaldehyde
72 g (0.29 mol) of 5-chloro-2,3,4-trifluorobenzal chloride are added to 220
g of 95% strength sulphuric acid at 40.degree., and stirring is continued
at 40.degree. until evolution of gas has finished.
The residue is poured onto ice, extracted with methylene chloride, and the
organic phase is dried with sodium sulphate, concentrated and distilled.
18 g (32% of theory) of 5-chloro-2,3,4-trifluorobenazldehyde of boiling
point 73.degree./15 mbar, n.sub.D.sup.20 : 1.5020 are obtained.
The following is obtained analogously:
3,5-dichloro-2,4-difluorobenzaldehyde, boiling point 98.degree.14 mbar,
melting point 32.degree..
It is understood that the specification and examples are illustrative but
not limitative of the present invention and that other embodiments within
the spirit and scope of the invention will suggest themselves to those
skilled in the art.
______________________________________
Example of a tablet containing end products tainable by using
the compounds of the invention
______________________________________
Each tablet contains:
Compound of Example 1 583.0 mg
Hicrocrystalline cellulose 55.0 mg
Maize starch 72.0 mg
Poly(1-vinyl-2-pyrrolidone) insoluble
30.0 mg
Highly disperse silica 5.0 mg
Magnesium stearate 5.0 mg
750.0 mg
The lacquer coating contains:
Poly(O-hydroxypropyl O-methyl)cellulose 15 cp
6.0 mg
Macrogol 4000 rec. INN (Polyethylene glycol DAB)
2.0 mg
Titanium (IV) oxide 2.0 mg
10.0 mg
______________________________________
The end products have very low toxicity and exhibit a broad antibacterial
spectrum towards Gram-positive and Gram-negative organisms, especially
towards enterobacteriaceae; especially including those which are resistant
to various antibiotics, such as, for example, penicillins, cephalosporins,
aminoglycosides, sulphonamides and tetracyclines.
These valuable properties make it possible to use them as chemotherapeutic
active compounds in medicine and as substances to preserve inorganic and
organic materials, especially organic materials of all types, for example
polymers, lubricants, dyes, fibres, leather, paper and wood, and
foodstuffs and water.
The end products are active against a very broad spectrum of
microorganisms. Using them, it is possible to control Gram-negative and
Gram-positive bacteria and bacteroid microorganisms and to prevent,
ameliorate and/or heal illnesses caused by these pathogens.
The end products are particularly active against bacteria and bacteroid
microorganisms. Thus, they are especially suitable for the prophylaxis and
chemotherapy of local and systemic infections caused by these pathogens in
human and veterinary medicine.
For example, local and/or systemic illnesses which are caused by the
following pathogens or by mixtures of the following pathogens can be
treated and/or prevented: micrococcaceae, such as Staphylococci, for
example Staphylococcus aureus, Staph. Epidermidis,
(Staph.=Staphylococcus); Lactobacteriaceae, such as Streptococci, for
example Streptococcus pyogenes, .alpha.- an .beta.-haemolytic
Streptococci, non-.gamma.-haemolytic Streptococci, Enterococci and
Diplococcus pneumoniae (Pneumococci) (Str.=Streptococcus);
Enterobacteriacea, such as Escherichiae bacteria of the Escherichia group,
for example Escherichia coli, Enterobacter bacteria, for example E.
aerogenes and E. cloacae (E.=Enterobacter), Klebsiella bacteria, for
example K. pneumoniae (K.=Klebsiella), Serratia, for example Serratia
marcescens, Proteae bacteria of the Proteus group: Proteus, for example
Pr. vulgaris, Pr. morganii, Pr. rettgeri and Pr. mirabilis (Pr.=Proteus);
Pseudomonadaceae, such as Pseudomonas bacteria, for example Ps. aeruginosa
(Ps.=Pseudomonas); Bacteroidaceae, such as Bacteroides bacteria, for
example Bacteroides fragilis Mycoplasma, for example Mycoplasma
pneumoniae, also Mycobacteria, for example Mycobacterium tuberculosis,
Mycobacterium leprae and atypical Mycobacteria.
The above list of pathogens is purely illustrative and is in no way to be
interpreted as restrictive. The following may be mentioned as examples of
illnesses which can be prevented, ameliorate and/or healed by the end
products: otitis, pharyngitis; pheumonia; peritonitis; pyelonephritis;
cystitis; endocarditis, systemic infections; bronchitis; arthritis; local
infections and septic illnesses.
The end products can be used as pharmaceutical preparations which in
addition to non-toxic, inert pharmaceutically vehicles contain one or more
compounds or which consist of one or more active compounds.
The end products can be used as pharmaceutical preparations in dosage
units. This means that the preparation are in the form of individual
parts, for example tablets, coated tablets, capsules, pills, suppositories
and ampoules, of which the content of active compound corresponds to a
fraction or a multiple of an individual dose. The dosage units can
contain, for example, 1, 2, 3, or 4 individual doses or 1/2, 1/3 or 1/4 of
an individual dose. An individual dose preferably contains the amount of
active compound which is given in one administration and which usually
corresponds to a whole, a half, or a third or a quarter of a daily dose.
By non-toxic, inert pharmaceutically suitable vehicles there are to be
understood solid, semi-solid or liquid diluents, fillers and formulation
auxiliaries of all kinds.
Tablets, coated tablets, capsules, pills, granules, suppositories,
solutions, suspensions and emulsions, pastes, ointments, gels, creams,
lotions, powders and sprays may be mentioned as preferred pharmaceutical
preparations.
Tablets, coated tablets, capsules, pills and granules can contain the
active compound or compounds alongside the customary vehicles such as (a)
fillers and extends, for example starches, lactose, sucrose, glucose,
mannitol and silica, (b) binders, for example carboxymethylcellulose,
alginates, gelatin and polyvinylpyrrolidone, (c) humectants, for example
glycerol, (d) disintegrating agents, for example agar-agar, calcium
carbonate and sodium carbonate, (e) solution retarders, for example
paraffin, and (f) absorption accelerators, for example quaternary ammonium
compounds, (g) wetting agents, for example cetyl alcohol or glycerol
monostearate, (h) adsorbents, for example kaolin and bentonite and (i)
lubricants, for example talc, calcium and magnesium stearate and solid
polyethylene glycols, or mixtures of these substances listed under (a) to
(i).
The tablets, coated tablets, capsules, pills and granules can be provided
with the customary coatings and shells, optionally containing opacifying
agents, and can also be of such composition that they release the active
compound or compound only, or preferentially, in a certain part of the
intestinal tract, optionally in a delayed manner, examples of embedding
compositions which can be used being polymeric substances and waxes.
The active end products, optionally together with one or more of the
abovementioned vehicles, can also be in a microencapsulated form.
Suppositories can contain, in addition to the active end products, the
customary water-soluble or water-insoluble vehicles, for example
polyethylene glycols, fats, for example cacao fat, and higher esters (for
example C.sub.14 -alcohol with C.sub.16 -fatty acids), or mixtures of
these substances.
Ointments, pastes, creams and gels can contain the customary vehicles in
addition to the active end products, for example animal and vegetable
fats, waxes, paraffins, starch, tragacanth, cellulose derivatives,
polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide
or mixtures of these substances.
Powders and sprays can contain the customary vehicles in addition to the
active end products, for example lactose, talc, silica, aluminium
hydroxide, calcium silicate and polyamide powders or mixtures of these
substances. Sprays can additionally contain the customary propellants, for
example chlorofluorohydrocarbons.
Solutions and emulsions can contain the customary vehicles in addition to
the active compound or compounds, such as solvents, solubilising agents
and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene
glycol, 1,3-butylene glycol, dimethylformamide, oils, especially
cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and
sesame oil, glycerol, glycerol-format, tetrahydrofurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, or mixtures of
these substances.
For parenteral administration, the solutions and emulsions can also be in a
sterile form which is isotonic with blood.
Suspensions can contain the customary vehicles in addition to the active
compound or compounds, such as liquid diluents, for example water, ethyl
alcohol or propylene glycol, suspending agents, for example ethoxylated
isostearyl alcohols, polyoxyethylene sorbitol esters and soribtan esters,
microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar
and tragacanth, or mixtures of these substances.
The formulation forms mentioned can also contain colourants, preservatives
and additives which improve the odour and flavour, for example peppermint
oil and eucalyptus oil, and sweeteners, for example saccharin.
The therapeutically active end products should preferably be present in the
abovementioned pharmaceutical preparations in a concentration of about 0.1
to 99.5, preferably of about 0.5 to 95, % by weight of the total mixture.
The abovementioned pharmaceutically preparations can also contain other
pharmaceutically active compounds in addition to the compounds according
to the invention.
The abovementioned pharmaceutically preparations are manufactured in the
usual manner according to known methods, for example by mixing the active
compound or compounds with the vehicle or vehicles.
The active end products preparations can be administered locally, orally,
parenterally, intraperitoneally and/or rectally, preferably orally or
parenterally, such as intravenously or intramuscularly.
In general, it has proved advantageous both in human medicine and in
veterinary medicine to administer the active compound or compounds in
amounts of about 0.5 to about 500, preferably 5 to 100, mg/kg of body
weight every 24 hours, optionally in the form of several individual
administrations, in order to achieve the desired results. An individual
administration contains the active compound or compounds preferably in
amounts of about 1 to about 250, especially of 3 to 60, mg/kg of body
weight. However, it can be necessary to deviate from the dosages mentioned
and in particular to do so as a function of the nature and body weight of
the subject to be treated, the nature and the severity of the illness, the
nature of the preparation and of the administration of the medicine, and
the time or interval over which the administration takes place.
Thus, it can suffice in some cases to manage with less than the
abovementioned amount of active end product, whilst in other cases the
abovementioned amount of active end product must be exceeded. The
particular required optimum dosage and the type of administration of the
active compounds can easily be decided by anyone skilled in the art, on
the basis of this expert knowledge.
The end products can be administered in the customary concentrations and
preparations together with the feed or with the feed preparations or with
the drinking water. By this means, it is possible to prevent, ameliorate
and/or heal an infection by Gram-negative or Gram-positive bacteria and by
this means to achieve a promotion of growth and an improvement in the
utilisation of the feed.
The MIC values of some of the end products are indicated in the table
below.
As a comparison, corresponding MIC values for
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
acid ("norfloxacin"), which is disclosed in J. Med. Chem. 23, 1358 (1980),
have been indicated, it emerging that the end products are superior to the
known compounds.
__________________________________________________________________________
MIC (mcg/ml)
Example No.
strain 1 2 3 5 6 7 8 10 17
__________________________________________________________________________
E. coli Neumann
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
./. .ltoreq.0.015
./.
T 7 .ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
0.025
./.
445/7 4 8 8 8 4 16 ./. 16 ./.
Klebsiella 63
.ltoreq.0.015
0.03
0.03
0.03
0.015
0.06
./. 0.125
./.
6179 0.03
0.03
.ltoreq.0.015
0.03
0.015
0.06
./. 0.06
./.
Proteus 1017
.ltoreq.0.015
./. ./. ./. 0.06
0.125
./. ./. ./.
Providencia 12012
.ltoreq.0.015
0.03
./. ./. 0.03
./. ./. ./. ./.
12052 8 16 16 32 4 16 ./. ./. ./.
Staph. FK 422
0.25
0.25
0.25
0.25
0.025
0.5 0.06
./. .ltoreq.0.015
1756 0.25
0.5 0.25
0.5 0.5 0.5 0.06
./. .ltoreq.0.015
133 0.25
0.25
0.25
0.5 0.25
0.25
0.06
./. ./.
Pseudom. Ellsworth
0.06
./. ./. ./. ./. ./. ./. ./. ./.
__________________________________________________________________________
MIC (mcg/ml)
Example No.
strain 12 13 14 17 19 20 21 22 Norfloxacin
__________________________________________________________________________
E. coli Neumann
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
./. .ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
0.06
T 7 .ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
./. .ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
.ltoreq.0.015
0.03
445/7 8 8 2 ./. 1 1 1 2 16
Klebsiella 63
.ltoreq.0.015
.ltoreq.0.015
0.06
./. 0.03
.ltoreq.0.015
0.06
0.03
0.125
6179 0.06
0.06
0.25
./. 0.03
0.03
0.03
0.06
0.25
Proteus 1017
0.03
.ltoreq.0.015
0.125
./. 0.03
.ltoreq.0.015
0.03
0.06
0.03
Providencia 12012
.ltoreq.0.015
.ltoreq.0.015
0.06
./. 0.03
0.03
0.06
0.06
0.03
12052 16 16 16 ./. 4 4 1 2 64
Staph. FK 422
0.25
0.25
./. .ltoreq.0.015
0.06
0.06
0.125
0.125
0.5
1756 0.25
0.25
./. .ltoreq.0.015
0.06
0.06
0.125
0.125
1
133 0.25
0.25
./. ./. 0.06
0.06
0.06
0.125
0.5
Pseudom. Ellsworth
0.125
0.125
./. ./. 0.125
0.25
./. ./. 0.125
__________________________________________________________________________
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